The present invention relates to a novel process for the conversion of (1R,4R) N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthaleneamine of formula 2, hereinafter referred to as cis (1R,4R) isomer, or trans (1S,4R), isomer of formula 3, or trans (1R,4S) isomer of formula 4, or mixtures thereof, to (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1,2,3,4-tetrahydro-1-naphthaleneamine of formula 1, commonly known as sertraline (INN Name). 
These aforesaid isomers of formulas 2, 3 and 4 are undesired stereoisomers of sertraline of formula 1, and are invariably co-produced during the manufacture of this drug by known processes such as that disclosed in U.S. Pat. No. 4,536,518, which is incorporated herein by reference. More particularly, the present invention relates to a novel process for recycling the undesired stercoisomers, both the trans isomers as well as the cis (1R,4R) isomer, to obtain sertraline in asymptotic amounts through an iterative process. Sertraline hydrochloride (commonly known as Zoloft(copyright)) is an important drug useful in the treatment of depression, obsessive-compulsive disorder and panic disorder.
Sertraline has two chiral centres and hence has four stercoisomeric forms, namely, the (1R,4R), (1S,4S), (1R,4S), and (1S,4R) isomeric forms of setraline. Of these, the active stercoisomer for therapeutic purpose is the cis (1S,4S) isomer of formula 1.
U.S. Pat. Nos. 4,536,518 and 4,556,676, assigned to Pfizer, disclose a multi-step process for synthesis of pure (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthaleneamine from 3,4-dichlorobenzophenone. The process proceeds via racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, a compound of formula 6. 
The ketone is condensed with methylamine to form a racemic imine mixture of formula 5c (shown below). The racemic imine is then reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to N-methyl-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthaleneamine, which is a racemic mixture of the cis and trans isomers. Trans isomers are separated from the cis isomers by fractional crystallization. Resolution of the separated cis racemate with optically active precipitant acid, such as D-(xe2x88x92)-mandelic acid in a classical manner, finally affords the desired cis-(1S,4S)-enantiomer (sertraline). The process has the disadvantage that large amounts of the undesired isomers of formulas 2, 3, and 4 are co-produced thereby lowering the overall yield of sertraline and increasing the production cost.
U.S. Pat. Nos. 4,777,288 and 4,839,104, assigned to Pfizer, disclose processes for the preparation of 4-(3,4-dichlorophenyl)-4-ketobutanoic acid in pure form and in high yield. The 4-(3,4-dichlorophenyl)-4-ketobutanoic acid is converted to racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, the compound of formula 6. Also, PCT International Publication No. WO 98/15516 discloses a process to prepare a compound of formula 6 in pure form by reacting xcex1-naphthol and o-dichlorobenzene wherein the amount of by-product 4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone is decreased below 1%. The racemic tetralone obtained by the processes of U.S. Pat. Nos. 4,777,288; 4,839,104, and WO 98/15516 may be converted to sertraline by the process disclosed in U.S. Pat. Nos. 4,536,518 and 4,556,676. The processes thus carry with them the prior art disadvantage in that large amounts of the undesired isomers of formulas 2, 3, and 4 are co-produced thereby lowering the overall yield of sertralille and increasing the production cost. U.S. Pat. No. 5,196,607 assigned to Pfizer discloses a multi-step process for preparing chiral (4S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone of formula 6a in pure form and high yield. 
Yet another method is described in U.S. Pat. No. 5,466,880 whereby the chiral tetralone is prepared in an elaborate five-step process starting from 4-(3,4-dichlorophenyl)-4-ketobutanoic acid. Tetrahedron, 48(47), 10239 (1992), provides another method for preparing the chiral (4S) tetralone by reduction of 4-ketobutanoic acid ester with an asymmetric carbonyl reducing agent. The preparation of chiral tetralone allows for major improvement in the overall synthesis of sertraline in that the unwanted cis (1R,4R) isomer and trans (1S,4R) isomer are not co-produced when (4S) tetralone is converted to sertraline by methods described in U.S. Pat. Nos. 4,536,518; 4,556,676; 4,777,288; and 4,839,104.
PCT International Publication No. WO 95/15299 (Pfizer) describes a method for preparing chiral (4S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone of formula 6a by asymmetric reduction of the corresponding racemic mixture with asymmetric ketone reducing agents, viz., chiral oxazaborolidine compounds to produce a mixture of cis and trans alcohols, from which the (4S) enantiomer is separated and oxidized to give the (4S) chiral tetralone. 
The remaining mixtures of alcohols are oxidized to produce (4R) tetralone of formula 6b, which is then isomerized to racemic mixture of formula 6, with a base and recycled. The (4S) tetralone is then converted to sertraline by methods described in U.S. Pat. Nos. 4,536,518; 4,556,676; 4,777,288; and 4,839,104.
The PCT International Publication No. WO 98/27050 discloses a three step process for the preparation of a mixture of sertraline and its cis (1R,4R) isomer using a novel N-oxide intermediate.
In a recent publication (Organic Lett., 1(2), 293 (1999) an enantioselective synthesis of sertraline using an anionic imine ring closure methodology is described starting from dichlorocinnamic acid.
In all the methods described above, eventual isomer separation is inevitable however, none of the methods discussed above provides methods for recycling the unwanted stereoisomers of sertraline. A process for recycling trans isomer of sertraline is described in U.S. Pat. No. 5,082,970. The process involves refluxing the trans isomer or a mixture with about an equal part by weight of the corresponding cis isomer with about 2 molar equivalents of a base such as potassium tert-butoxide for 48 hours in an inert polar solvent to afford a cis-trans mixture in a ratio of about 2:1. However, this method appears to have certain drawbacks in that
i) an excess of base (2 mole equivalents) is used,
ii) it requires 48 hours of reflux, and, most importantly,
iii) the method is not exemplified with cis isomer containing (1R) center, which, incidentally, is the major unwanted isomer that is co-produced in equal amounts along with the desired cis-(1S) isomer. An experiment performed by the inventors herein on the cis (1R,4R) isomer, under the conditions described in the above-referred patent, did not result in isomerization at the C-1 center. This is understandable since the hydrogen at the C-1 position in sertraline isomers is not reactive under the conditions described, and hence is not susceptible to isomerization.
It is therefore, the object of the present invention to develop an alternate simple process whereby the unwanted isomers, both trans as well as the cis (1R,4R) isomer could be recycled to produce ultimately the desired cis (1S,4S) isomer in a simple manner which is commercially feasible.
The process of the present invention provides a method for converting the stereoisomers of sertraline into sertraline itself and comprises the steps of:
I. Converting cis (1R,4R) isomer of formula 2, or trans (IS,4R) isomer of formula 3, or mixtures thereof, to the corresponding (4R)-imine of formula 5a;
OR
xe2x80x83Converting trans (1R,4S) isomer of formula 4 to the corresponding (4S)-imine of formula 5b;
OR
xe2x80x83Converting a mixture of isomers of formulas 2 and 4, or a mixture of isomers of formulas 3 and 4, or a mixture of isomers of formula 2, 3 and 4, to the corresponding mixture of (4R)-said (4S)-imines of formula 5c;
II. Subjecting the (4R)-imine of formula 5a (if it has been produced in step I) to base catalyzed isomerization to produce a racemic imine mixture of formula 5c; and
III. Reducing of the mixture of (4R)- and (4S)-imines of formula 5c to obtain a mixture of sertraline with stereoisomers of formula 2, 3 and 4;
OR
xe2x80x83Reducing the (4S)-imine of formula 5b obtained in step I to obtain a mixture of sertraline and trans (1R,4S) isomer of formula 4.
Following step III, sertraline is separated from the reaction mixture, e.g., by fractional crystallization, and resolved, if necessary from the cis (1R, 4R) isomer. Thereafter or simultaneously, steps I, II, and III are repeated in an interative procedure so that sertraline is produced in an asymptotic yield.
The process described in this invention permits convenient recycling of the unwanted steroisomers of sertraline on a commercial scale as the entire process is simple and requires inexpensive raw materials.
The inventive process may also be described as a method for producing sertraline comprising:
(1) starting with an initial reaction mixture containing at least one sertralinc stereoisomer, converting said sertraline stereoisomer into an imine form of sertraline;
(2) reducing the imine form of sertraline into sertraline and at least one stereoisomer of sertraline;
(3) recovering sertraline from the reaction mixture; and
(4) repeating steps (1), (2), and (3).
In one embodiment, the initial reaction mixture contains the cis (1R, 4R) stereoisomer of sertraline (formula 2) and/or the trans (1S, 4R) stereoisomer of sertraline (formula 3) which are first converted into the (4R)-imine (formula 5a) form of sertraline, which is then converted into a mixture of (4R)- and (4S)-imines of formula 5c before being converted into sertraline.
In another embodiment, the initial reaction mixture contains the trans (1R, 4S) stereoisomer of sertraline (formula 4) which is converted into the (4S)-imine of formula 5b before being converted into sertraline.
The process described herein may be illustrated in the following schematic diagram: 
The present invention relates to a process whereby the unwanted isomers, both trans isomers as well as the cis (1R,4R) isomer, of sertraline, are converted to the desired cis (1S,4S) isomer in a manner, which is simple, convenient, easily scaleable and commercially feasible. The inventive process differs from prior art methods of producing sertraline in that it proceeds by converting unwanted stereoisomers of sertraline into sertraline. The unwanted stereoisomers are first converted into an imine form of sertraline which eliminates the chirality at the C-1 position. The imine formed is stable and does not hydrolyze to ketone under the conditions of the present invention. This step is quite useful in comparison to prior art methods because it obviates the need to convert a ketone into an imine (when ketone is one of the intermediates produced). Once the imine is formed, it is then necessary to isomerize the C-4 position since the (4R) components are the major unwanted stereoisomers in the starting mixture. Isomerization is achieved under base catalyzed conditions in a very facile manner, a process hitherto unreported.
Thus, the process of the present invention is illustrated in Scheme I and comprises the steps of:
I. Converting cis (1R,4R) isomer of formula 2, or trans (1S,4R) isomer of formula 3, or mixtures thereof, to the corresponding (4R)-imine of formula 5a;
OR
xe2x80x83Converting trans (1R,4S) isomer of formula 4 to the corresponding (4S)-imine of formula 5b;
OR
xe2x80x83Converting a mixture of isomers of formula 2 and 4, or a mixture of isomers of formula 3 and 4, or a mixture of isomers of formula 2, 3 and 4, to the corresponding mixture of (4R)- and (4S)-imines of formula 5c;
II. If the (4R)-imine of formula 5a has been produced in Step I, subjecting the (4R)-imine of formula 5a to base catalyzed isomerization to produce a racemic imine mixture of formula 5c;
III. Reducing the mixture of (4R)- and (4S)-imines of formula 5c to obtain a mixture of sertraline with isomers of formula 2, 3, and 4;
OR
xe2x80x83If the (4S)-imine of formula 5b has been produced in Step I, reducing the (4S)-imine of formula 5b to obtain a mixture of sertraline and trans (1R,4S) isomer of formula 4.
Following these steps, sertraline of formula 1 is separated from the reaction mixture and, if necessary, resolved from the cis (1R, 4R) isomer. The unwanted byproduct isomers are recycled through the same steps to produce setraline in asymptotic yield.
According to the process of the present invention, in step I of the process cis (1R,4R) isomer of formula 2, or trans (1S,4R) isomer of formula 3, or mixtures thereof is/are converted to the corresponding (4R)-imine of formula 5a; or trans (1R,4S) isomer of formula 4 is converted to the corresponding (4S)-imine of formula 5b; or a mixture of stereoisomers of formulas 2 and 4, or a mixture of stereoisomers of formulas 3 and 4, or a mixture of stereoisomers of formulas 2, 3 and 4, are converted to a mixture of (4R)- and (4S)-imines of formula 5c. The conversion may be carried out by oxidation in the presence of a base using a halogen ion generating reagent such as N-haloamides, N-haloimides and N-halohydantoins. Step I of the process is preferably carried out by oxidation using a hypohalite. The preferred halogen ion generating reagents are N-bromosuccinimide and N-chlorosuccinimide. The hypohalite may be added to the reaction mixture or generated in-situ by reaction of a halogen with a base preferably in a protic solvent. Examples of bases that may be used include alkali metal hydroxides such as LiOH, NaOH, KOH, CsOH; and alkali metal carbonates such as Li2CO3, Na2CO3, K2CO3. The preferred bases that can be employed are alkali metal hydroxides such as LiOH, NaOH, KOH, CsOH. The most preferred is NaOH. The protic solvents that may be used include aqueous or alcoholic solvent(s) or mixtures thereof. The most preferred solvent is methanol.
According to the process of the present invention, in step II of the process, the (4R)-imine of formula 5a (if it has been produced in step I) is subjected to base catalyzed isomerization to yield a racemic imine mixture of formula 5c. Base catalyzed isomerization may be carried out by using non-nucleophilic organic bases. Examples of non-nucleophilic organic bases that may be used include metal alkoxides, metal amides, dimsyl or trityl metal salts, and the like. Preferably, the non-nucleophilic organic base is a metal alkoxide; more preferably an alkali metal alkoxide; most preferably potassium tert-butoxide. Preferably, the alkali metal alkoxide is used in a mole ratio of about 5% to about 20%, preferably 10%, with respect to the imine. The solvent for the isomerization reaction is an aprotic solvent that may include ethers, acyclic or cyclic, such as diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like. The preferred solvents are ethers such as tetrahydrofuran and 1,4-dioxane. The most preferred solvent is tetrahydrofuran. The temperature for the isomerization reaction may range from ambient to about 140xc2x0 C., preferably about 70xc2x0 C. to about 75xc2x0 C. The reaction time ranges from 1 to 10 hours, preferably about 2 to about 3 hours. After the reaction is completed, the reaction mixture is concentrated and degassed, an appropriate quantity of water is added, and the isomerized racemic imine is isolated by filtration. In the case where the solvent used for the reaction is immiscible with water, the reaction mixture is simply washed with an appropriate quantity of water, and the solvent is degassed to recover the isomerized racemic imine.
According to the process of the present invention, step III comprises reduction of the mixture of (4R)- and (4S)-imines of formula 5c to obtain a mixture of sertralinc with stereoisomers of formulas 2, 3, and 4; or reduction of (4S)-imine of formula 5b (if it was obtained in step I) to obtain a mixture of sertraline and trans (1R,4S) isomer of formula 4. Reduction may be achieved by the use of a metal hydride complex or by means of catalytic hydrogenation. Preferably, the mixture of (4R)- and (4S)-imine of formula 5c or the (4S)-imine of formula 5b is reduced by catalytic hydrogenation. Catalytic hydrogenation results in a mixture of stereoisomers wherein the cis isomer(s) are present in amounts greater than the trans isomer(s). More preferably, the imine(s) is/are catalytically hydrogenated to get predominantly the cis isomers, along with minor quantity of trans isomers. The catalytic hydrogenation is preferably carried out in protic solvents such as primary, secondary, tertiary alcohols or mixtures thereof. Examples of the hydrogenation catalysts that may be used include Raney Nickel or precious metal promoters such as platinum or palladium on supports such as carbon, graphite, calcium carbonate, and the like. The catalytic hydrogenation may also be carried out using copper containing catalysts such as copper chromite in aprotic solvents, particularly ethers such as tetrahydrofuran.
Separation of the cis and trans isomers and subsequent resolution of cis (1R,4R) and (1S,4S) stereoisomers, or of trans (1R,4S) and (1S,4R) stereoisomers as their hydrochlorides, is carried out by methods well known to those skilled in the art and heretofore described in the literature, e.g., cis isomers may be separated from a mixture of cis and trans isomers by fractional crystallization or chromatography; and resolution of the cis (1S,4S) and cis (1R,4R) isomers may be achieved by treating a solution of cis-racemate free base with an optically active precipitant acid such as D-(xe2x88x92)-mandelic acid and precipitating the less soluble diastereomeric salt.
According to a preferred embodiment of the present invention, the undesired isomers of sertraline are recycled by a process comprising the following steps:
a. Isolation of a mixture of sertraline and cis (1R,4R) isomer from the mixture of sertraline with stereoisomers of formulas 2, 3, and 4 obtained in step III; followed optionally by repetition of steps I, II and III, or by repetition of steps I and III on the mixture of trans (1R,4S) and trans (1S,4R) isomers;
OR
xe2x80x83Isolation of sertraline from the mixture of sertraline and trans (1R,4S) isomer of formula 4 obtained in step III; followed optionally by repetition of steps I and III on the trans (1R,4S) isomer;
b. Resolution of the mixture of sertraline and cis (1R,4R) isomer of formula 2 obtained in step a; followed optionally by repetition of steps I, II, and III on the cis (1R,4R) isomer; and
c. Resolution of the mixture of trans (1R,4S) and trans (1S,4R) isomers obtained in step a; followed optionally by repetition of steps I, II and III on the trans (1S,4R) isomer and repetition of steps I and III on the trans (1R,4S) isomer.
The process described in this invention, thus permits convenient recycling of the unwanted steroisomers of sertraline to the desired (1S,4S) sertraline in asymptotic amounts through iteration. The process described is feasible on a commercial scale in view of the fact that the operations involved are simple and the raw materials required are not expensive.